The abuse of cocaine is widely recognized to be an extremely serious health and social problem of epidemic proportions for which there is no effective treatment. As part of our collaborative studies on the structure and function of the mammalian central nervous system (CNS), we have shown that GBR 12909 is a slowly dissociating, high affinity inhibitor of dopamine uptake. This drug largely blocks cocaine elevation of extracellular dopamine in the nucleus accumbens of rats as measured by in vivo microdialysis. We also showed that GBR 12909 prevents cocaine self-administration in rhesus monkeys trained to self-administer cocaine with no effect on normal behavior as measured by food maintained responding. We have now utilized positron emission tomography (PET) to validate and extend these studies by showing that doses of GBR 12909 which greatly reduce cocaine self-administration in monkeys produce high dose related occupation of dopamine transporters. These studies strongly suggest that GBR 12909 produces suppression of cocaine self- administration by occupancy of the dopamine receptor and that this drug and/or its congeners may be of substantial value in the treatment and prevention of human cocaine abuse. In other studies, we continued the design, chemical synthesis and evaluation of delta opioid receptor agonists and antagonists as potential analgesics and drugs for the treatment and prevention of cocaine and narcotic abuse. One of these drugs is SNC 80, which we have found to be a highly selective delta opioid receptor agonist. We have now shown that it has no effect in several measures of immune function in the rat while elevating others suggesting that delta opioid ligands may be useful in pain management in normal and immunocompromised individuals. Our chemical synthesis studies have resulted in the following advances: Novel methodology for the N-deprotection and O- demethylation of opium alkaloids and derivatives; synthesis of 3- substituted-3-deoxynaltrindole derivatives; a novel synthesis of thebaine from codeine; and a direct and simple conversion of codeine to thebainone-A and dihydrothebainone. Finally, we have developed novel drugs as tools for study of corticotropin releasing hormone (CRH) receptors including potential agents for PET and single photon emission computed tomography (SPECT) imaging of CRH receptors in living animals and humans.